1. Field of the Invention
The present disclosure relates generally to the fields of diagnostic testing and imaging agents. The disclosure provides, for example, novel ligands that are useful for the preparation of novel dual-modality imaging agents for radioisotope-based imaging (PET or SPECT) and MRI, said novel imaging agents, and methods of synthesis and methods of use thereof.
2. Description of Related Art
Molecular imaging is used for visualizing biological targets and to understand their complexities for diagnosis and treatment purposes. Through an accurate and real-time imaging of biological targets, a thorough understanding of the fundamental biological processes can be gained leading to the successful diagnose of various diseases (Weissleder, 2006). Every imaging modality on its own fails to deliver all the necessary information about the biological target. Therefore, attempts are being made to combining two or more imaging modalities to overcome shortcomings present in single-modality system and to enhance the quality of the images to achieve proper visualization of the organs and a better reliability of the collected data. Multimodal imaging techniques are increasingly becoming popular and a variety of different combinations, such as MRI/optical, PET/near-infrared optical fluorescence (NIRF) and PET/CT and PET/MRI have been reported (Jennings, et al., 2009; Ntziachristos, et al., 2000; Beyer, et al., 2000; Murray, et al., 1993; Link and El-Sayed, 1999; Alivisatos, 1996). The fusion of PET and MRI is especially desirable as they mutually complement each other. While radioisotope-based techniques (PET or SPECT) are sensitive and therefore allow the study of processes at the molecular and cellular level in vivo, their spatial resolution is poor (≧1 cm for a clinical scanner) (Catana, et al., 2006; Chemy, 2006; Chemy, 2001). On the other hand, non radioisotope-based techniques such as MRI provide excellent spatial resolution (<0.1 cm), but require much larger amounts of contrast agent (Caravan, et al., 1999; Raymond and Pierre, 2004; Seo, et al., 2006). The need to overcome their respective disadvantages drives the ongoing efforts to develop dual modality imaging instruments and agents so that the strengths of these techniques can be synergistically combined to provide accurate physiological and anatomical information.
To take advantage of bimodal PET (or SPECT)/MRI imaging, a dual modality agent with a “single pharmacological behavior” is desirable, which that can combine the high sensitivity of PET and the high resolution of MRI. For instance, a MRI/PET probe should enable the increased accuracy of probe co-location and cross-validation of MRI and PET agents in target regions of interest (two measures of one event). While MRI scan can provide the exact location of the probe, motion artifact correction, and PET partial volume correction, the PET part can afford better image quantification for higher detection sensitivity and more accurate molecular signature changes over the course of treatment. In addition, the perfect collocation of MRI and PET signals would enable the co-registration of MRI and PET images. Given the proton MRI contrast can be viewed as the ups and downs of the proton ocean, a co-localized PET signal distinct from the background ocean could make the MRI contrast more identifiable, which further improves the MRI sensitivity.
Gadolinium is a known and well characterized T1 contrast agent with useful and important physical properties for use in MRI imaging agents. Unfortunately, this ion is highly toxic in a “free” state, and hence it is always used as a thermodynamically stable and kinetically inert complex. Linear polyamine diethylenetriaminepentaacetic acid (DTPA) or polyazamacrocycle 1,4,7,-10-tetraazacyclododecane-1,4,7,10-tetraacetic acid derivatives (DOTA) with coordinating acetate arms have been commercially employed as they form sufficiently stable Gd(III) complexes. Unfortunately, these low molecular weight contrast agents are nonspecific, undergo rapid renal excretion and extravasation, and they have relatively low relaxivity. To compensate for the low signal enhancement generated by DTPA and DOTA gadolinium complex, most targeted gadolinium compounds have relied on the development of nano platforms that can carry a high payload of gadolinium, by which the longitudinal relaxivities (r1) per gadolinium can be further enhanced as the rotational correlation time increases with the molecular weight. A wide range of macromolecules and other nanoparticulate systems have been tested as platforms for gadolinium labeling, including dendrimers, (Boswell, et al., Kobayashi and Brechbiel, 2005; Langereis, et al., 2006a; Langereis, et al., 2006b; Langereis, et al., 2007; Ruovský, et al., 2006; Bolskar, 2008; Zhu, et al., 2008) polymers, (Duarte, et al., 2001) emulsions, (Morawski, et al., 2004) silica nanoparticles, (Lin, et al., 2004; Rieter, et al., 2007a; Rieter, et al., 2007b; Santra, et al., 2005) and vesicles (Cheng and Tsourkas, 2008; Hak, et al., 2009; Terreno, et al., 2008; Unger, et al., 1989). Some of these agents have relaxivities on the order of 105 to 106 mM−1 s−1 per nanoparticle (Morawski, et al., 2004; Santa, et al., 2005; Cheng and Tsourkas, 2008). Of all the systems, dendrimers have a specified molecular structure and formula and have been used extensively. PAMAM is the favored choice in dendrimers but Gd-PAMAM complexes rarely give an ionic relaxivity greater than 11 mM−1 S−1 (Venditto, et al., 2005; Kobayashi and Brechbiel, 2003) Researchers at Schering AG (Berlin, Germany) developed another class of dendritic contrast agents: Gadomer-17, a polylysine-based contrast agent (MW 17,453) with 24 gadolinium-1,4,7,10-tetrakis(carboxymethyl) cyclododecane (Gd-DOTA) complexes (Dong, et al., 1998; Nicolle, et al., 2002). Gadomer-17 has an ionic relaxivity of 17.3 mM−1 s−1 (20 MHz, 39° C.).
Numerous nanoparticle based MRI/PET agent have been reported and have shown considerable promise. These nanoparticles show a high relaxivity (Morawski, et al., 2004; Santa, et al., 2005; Cheng and Tsourkas, 2008) relative to other MRI/PET agents. However, using nanoparticle for MRI/PET probe development presents its own challenges. Often, nanoparticle constructs used for MRI/PET have questionable in vivo stability or integrity. Clinically used contrast agents used are desired to have rapid diffusion (short distribution half-life tα1/2) relatively long blood circulation time (long elimination half-life tβ1/2), and little nonspecific accumulation in the body (renal clearable) after systemic administration. These specific pharmacokinetic features may ensure the success of clinical imaging processes but also may minimize the potential health hazards caused by the introduction of contrast agents. Most nanoparticle are unsuitable for clinical use as reticuloendothelial system (RES) organs often rapidly sequester these nanostructures, resulting in slow RES clearance processes and potential health hazards (Cheng, et al., 2011; Chen, et al., 2005; Gao, et al., 2004). These limitations in pharmacokinetics of nanoparticles significantly hamper their clinical applications. Thus, it is desirable to develop probes that possess improved distribution properties as well as improved pharmacokinetic properties.